Abstract
A convenient synthetic approach to novel functionalized bis(isoxazoles), the promising bivalent ligands of the AMPA receptor, was elaborated. It was based on the heterocyclization reactions of readily available electrophilic alkenes with the tetranitromethane-triethylamine complex. The structural diversity of the synthesized compounds was demonstrated. In the electrophysiological experiments using the patch clamp technique on Purkinje neurons, the compound 1,4-phenylenedi(methylene)bis(5-aminoisoxazole-3-carboxylate) was shown to be highly potent positive modulator of the AMPA receptor, potentiating kainate-induced currents up to 70% at 10−11 M.
Highlights
An isoxazole ring occurs in various natural and synthetic compounds with a wide spectrum of biological activities [1]
When selecting and prioritizing potential thechemotypes synthesis and biological evaluation, we considered the pharmacophore and chemotypes the synthesis biological evaluation, considered pharPAM
We report the synthesis of the desired compounds, as well as the results of their electroreport the synthesis of the desired compounds, as well as the results of their electrodesired compounds, well ascompounds, the results of electrophysiological the report the synthesis of theasdesired as their well as the results of their evaluation, electrophysiological evaluation, molecular modeling aiming to elucidate mechanism physiological evaluation, the the molecular modeling aiming to elucidate elucidate the the mechanism of of of molecularevaluation, modeling the aiming to elucidate the aiming mechanism of action, and the prediction physiological molecular modeling to the mechanism of action, and prediction of their physico-chemical action, and the the prediction ofand their physico-chemical andand their physico-chemical action, and the prediction of their physico-chemical and
Summary
An isoxazole ring occurs in various natural and synthetic compounds with a wide spectrum of biological activities [1]. Involved in many significant neurophysiological processes related to the fast synaptic excitatory transmission, memory formation, etc., the AMPA receptor is a promising pharmacological target [14,15]. Its positive allosteric modulators (PAMs) are potential candidates for the development of cognition enhancers and drugs against the Alzheimer’s and Parkinson’s diseases, multiple sclerosis, soft cognitive disorders, age-related cognition and memory impairments, autism, depression, drug addiction, etc. The creation of compounds acting as allosteric modulators of AMPA receptors is currently one of the most promising directions for the progress of neuropharmacology
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